Updated 7 May 2008

The prognosis for most cases of extensive stage SCLC is guarded and treatment is palliative. Without chemotherapy, the average survival is only 8-10 weeks. Thoracic radiotherapy alone may palliate local symptoms but has little impact on survival. The majority of patients (70-80%) respond to chemotherapy and complete responses occur in 15-20%. Median survival with standard regimens is 8-11 months. Prophylactic cranial irradiation in patients responding to chemotherapy extends survival. Almost all patients relapse and less than 5% are alive at 2 years. The small proportion (1-2%) of long-term survivors usually had low bulk metastatic disease and an exceptional response to chemotherapy.

Standard Chemotherapy of Extensive Stage SCLC

Guideline: Combination chemotherapy is superior to monotherapy in SCLC.

Level of Evidence: I

Monotherapy with oral etoposide has been proved inferior to combination chemotherapy in SCLC (Souhami, 1997). Combination chemotherapy should be recommended to all extensive SCLC patients fit enough to receive it. However, randomised trials of various combination chemotherapy protocols have not demonstrated a superior regimen.

Standard regimens are the same as for limited SCLC (see above 6.4.2.1) including four cycles of sequential platinum plus etoposide (Protocol LUSCPE). Although cyclophosphamide and doxorubicin regiments (LUSCCAV) perform as well as platinum and etoposide in the extensive stage setting, six cycles of non-platinum containing chemotherapy appear required to generate a similar result (Roth).

Frail or elderly patients that are judged unsuitable for intravenous combination chemotherapy or refuse such therapy may derive some palliative benefit from oral etoposide (LUSCPOE).

References:

1. Souhami RL, Spiro SG, Rudd RM et al: Five day oral etoposide treatment for advanced small-cell lung cancer: randomized comparison with intravenous chemotherapy. J Natl Cancer Inst 89:577-80, 1997.
2. Ihde DH: Chemotherapy for lung cancer. N Engl J Med 327:1434-1441, 1992
3. Roth B, Johnson D, Einhorn L, et al. Randomized study of cyclophosphamide, doxorubicin and vincristine versus etoposide and cisplatin versus alternation of these two regimens in extensive small cell lung cancer: A phase III trial of the Southeastern Cancer Study Group. J Clin Oncol 10:282-291, 1992.

Radiotherapy for Extensive Stage SCLC

Thoracic irradiation is not routinely recommended for patients with extensive stage SCLC that achieve satisfactory palliation with chemotherapy. Integrated chemoradiation may be used for selected patients with equivocal, minimal or "regional" extensive stage (pleural effusion, contralateral supraclavicular nodes, cervical nodes).

Guideline: Prophylactic cranial irradiation for extensive stage small cell lung cancer with response to chemotherapy decreases the risk of brain metastases and prolongs survival.

Level of Evidence: 2

One randomized trial in extensive stage SCLC responding to induction chemotherapy showed PCI to cause an impressive reduction in symptomatic brain metastases, with a hazard ratio of 0.27 (p<0.001). Overall survival was also improved (HR 0.68, p=0.003) with PCI with a 1-year survival from time of randomization of 27.1% in the treated group and 13.3% in the untreated group (Slotman). PCI radiotherapy dose in extensive SCLC responders is 25 Gy in 10 fractions or 20 Gy in 5 fractions.

Patients with brain metastases have traditionally received therapeutic brain irradiation followed by chemotherapy but it is now clear that brain metastases respond to chemotherapy and good performance status patients can be palliated with chemotherapy followed by therapeutic brain irradiation. Urgent therapeutic brain irradiation is recommended for rapidly evolving or more severe neurological deficits.

Palliative radiotherapy for locally advanced or metastatic SCLC is guided by the same principles as NSCLC (see above 6.4.1).

Reference:

1. Slotman B, Faivre-Finn C, Kramer G, et al. Prophylactic cranial irradiation in extensive small-cell lung cancer. N Engl J Med 357:664-72, 2007

Drug Selection and New Agents for Extensive Stage SCLC

Drug selection for SCLC chemotherapy regimens has traditionally involved permutations of five drugs or their analogues including: cyclophosphamide, doxorubicin, vincristine, etoposide and cisplatin. Cyclophosphamide and anthracycline combinations are infrequently used and most patients receive a platinum analogue (cisplatin or carboplatin plus etoposide.

A number of other chemotherapeutic agents have been shown to be active in SCLC including the taxanes (docetaxel and paclitaxel), gemcitabine, topoisomerase-1 inhibitors (irinotecan, topotecan), pemetrexed and amrubicin (Murray). Irinotecan and cisplatin have demonstrated superior results to etoposide and cisplatin in one Japanese study (Noda et al.) but it has not been possible to show superiority of irinotecan or topotecan containing regimens in North American SCLC populations(Hanna). Three drug combinations have been compared to two drug combinations but survival is not improved in extensive SCLC and the three drug combinations are definitely more toxic. Cisplatin or carboplatin plus etoposide remain standard (Protocol LUSCPE). A limited number of molecularly targeted agents have been tested in phase II trials but none have yet shown suggestive evidence of a worthwhile contribution to survival outcomes.

References:

1. Murray N, Turrisi A. A review of first-line treatment for small-cell lung cancer. J Thorac Oncol. 1:270-278, 2006
2. Noda K, Nishiwaki Y, Kawahara M, et al: Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small cell lung cancer. N Engl J Med 346:856-91, 2002
3. Hanna N, Bunn P, Langer C, et al. Randomized phase III trial comparing irinotecan/cisplatin with etoposide/cisplatin in patients with previously untreated extensive-stage disease small-cell lung cancer. J Clin Oncol 24:2038-2043.